Sympathetic nervous system activation
Healthy adults display lower sympathetic nervous system (SNS) activity during sleep than during wake-time. In contrast, OSA patients exhibit high level of sympathetic nervous system activity during both wake-time and sleep, accompanied by higher levels of circulating catecholamines [
281,
282]. Both human and animal models of IH reproduce this phenotype. Indeed, IH exposure has been shown to increase sympathetic nervous system activity in healthy humans [
283] and in rodents [
284,
285]. Oxidative stress, increased HIF-1α signaling and decreased HIF-2 signaling as well as endothelin-1 have been proposed as key mechanisms in IH-induced SNS activation [
286].
Increased sympathetic tone strongly impacts lipid and glucose metabolism, through circulating factors as well as neural innervation of the liver, pancreas, skeletal muscle and white adipose tissue [
287-
289], depicted in Figure
2. Adrenal epinephrine released during sympathetic activation triggers glucose production and impairs insulin secretion, thereby promoting insulin resistance [
290]. Consistently, sympathetic nervous system inhibition by carotid body denervation abolished insulin resistance in a rat model of diet induced obesity [
291] and abolished IH-induced fasting hyperglycemia and HOMA-IR elevation [
292]. Moreover, epinephrine, and to a lesser degree norepinephrine, have been largely studied and acknowledged as crucial mediators of adipose tissue lipolysis [
293,
294] acting through several β-adrenoceptor subtypes [
295,
296]. It is therefore tempting to postulate that IH-induced lipolysis and insulin resistance might be mediated through sympathetic nervous system activation. Finally, sympathetic innervations could be involved in hepatic glucose release [
297] and in muscle insulin resistance [
298]. In human volunteers, a 5 hour IH exposure induces a decrease in insulin sensitivity along with an increase in sympathetic nervous system activity but to date no causal link has been demonstrated [
255]. Even though using α-blockers or inhibiting epinephrine release by adrenal medullectomy improved glucose tolerance [
299,
300] and phentolamine treatment additionally prevented impairments in insulin secretion induced in mice by IH [
299], the impact of IH on insulin sensitivity seems to be independent of autonomic activity as neither medullectomy, phentolamine treatment or administration of SNS blocking agent hexamethonium improved IH-induced insulin resistance in mice [
252,
299,
300]. More studies are therefore needed to clarify the involvement of SNS activation in IH-induced metabolic dysregulation.
Sleep fragmentation
Apneic episodes, a cornerstone of OSA, are associated with bouts of increased brain activity (arousals) leading to repetitive partial or full awakenings and thus, sleep fragmentation [
301]. Taking into consideration the multiple detrimental metabolic consequences of intermittent hypoxic exposure, the obvious question with important clinical and therapeutic implications has been asked: does sleep fragmentation per se, without concomitant hypoxemia contribute to the development of metabolic impairments observed in OSA?
Sleep fragmentation represents a situation where total sleep duration is preserved, but continuous sleep and its architecture is interrupted by internal (e.g. arousals in OSA) or external (e.g. auditory stimuli in experiments) factors. Experimental studies using sleep fragmentation paradigm showed, that disruption of sleep by auditory and mechanical stimuli for two to three nights decreased insulin sensitivity [
302-
304], which was not compensated by increased insulin secretion [
303], suggesting that such exposures compromise fundaments of glucose homeostasis and induce impairments typical for pathogenesis of T2DM.
Epidemiological studies support the experimental evidence. Number of arousals was closely associated with fasting insulin levels and insulin resistance even after adjustments for age and severity of adiposity in young adults [
301] and EEG cues of wake/sleep transitions were associated with decreased insulin sensitivity and impaired insulin secretion independently of age, sex, body mass index, sleep stages, the arousal index, and the apnea-hypopnea index [
305]. Importantly, it was observed that sleep fragmentation exerts a negative impact in subjects with clinically manifested diabetes, as suggested by a community-based study investigating middle-age adults assessing sleep using wrist actigraphy which demonstrated that sleep fragmentation was associated with higher fasting glucose and insulin levels as well as with reduced insulin sensitivity in patients with T2DM, but not in non-diabetics [
56]. Additionally, sleep of patients with T2DM is characterized by higher sleep fragmentation scores detected by wrist actigraphy [
306].
Mechanisms linking sleep fragmentation to altered metabolic control probably include elevated night and morning cortisol levels [
302,
307] as well as sympathetic activation [
302]. Additionally, sleep fragmentation is independently associated with increased adiposity [
308] and less weight reduction during weight loss program [
309]. Experiments performed in rodent models of acute and prolonged (2 weeks) sleep fragmentation confirmed increased adiposity, insulin resistance, hyperglycemia and impaired insulin secretion [
310-
312]. Additionally, animal demonstrated increased markers of inflammation and oxidative stress in adipose tissue, in parallel to elevated corticosteroid levels [
310,
313]. Sleep fragmentation in mice also induced changes in visceral adipose tissue transcriptome with modifications in signaling and metabolic pathways including glucose metabolism [
314] and adipocyte differentiation [
315], however it is not known, whether these changes happen also in humans. Besides endocrine effects, sleep fragmentation seems to also have epigenetic effects demonstrated by insulin resistance and increased body weight of offspring of pregnant dams exposed to sleep fragmentation [
316].
Sleep fragmentation is typically accompanied by a reduction in slow-wave sleep duration, which represents another mechanism for impaired glucose metabolism. It has been proposed that slow-wave sleep is particularly important for metabolic homeostasis as selective suppression of slow-wave sleep (SWS), without perturbation of total sleep time, resulted in glucose intolerance, insulin resistance and impaired β-cell function [
303]. Selective SWS suppression (but not REM sleep suppression) also elevated morning glucose and insulin levels and impaired post-prandial glucose homeostasis in healthy men [
317]. Furthermore, sleep fragmentation impaired satiety perception, impaired insulin and glucagon-like peptide 1 response to meals [
304] and reduced fat oxidation [
318], making subjects prone to adipose tissue accumulation, especially under conditions of reduced satiety perception [
304]. The importance of SWS in glucose homeostasis is further supported by cross-sectional studies documenting that SWS duration is strongly predicting glucose-induced insulin secretion in obese individuals [
43] as well as by studies reporting shorter SWS in T2DM compared to nondiabetic subjects [
58]. Importantly, duration of SWS was negatively associated with HbA1c levels also in T1DM patients [
319], suggesting a global position of SWS in the regulation of glucose metabolism, independently of obesity or pathogenesis of T2DM. In contrast, REM sleep duration seems to be more related to energy homeostasis, as reduction in REM sleep is associated with obesity in children and adults [
320-
322], which could be at least partly explained by increased metabolic rate during REM sleep, which is lost with REM time reduction [
323].